The primary goal of this proposal is to increase the pace of experimental determination of the function of large and high priority gene families in bacterial genomes. These genes can help elucidate the mechanisms of antibiotic resistance, provide new drug targets or improve our understanding of the human microbiome. Specifically, we propose to catalyze the formation of a consortium of experimental and computational biologists that would collaborate directly to test experimentally the predicted functions of high-priority genes of currently unknown function or specificity. Central to this effort would be the creation of a community web-based database (portal) which would allow computational and experimental scientists to communicate easily, assist experimentalists in identifying those high-priority genes for which there are the highest- quality computational predictions for their molecular function, and providing feedback to the computational biologists, since it remains true that the insights and experience of the dedicated biochemist can be essential in guiding the development of algorithmic sophistication. Experimental validations of gene function would be reported in a manuscript when successful, or as annotations in the prediction database when negative. Many existing groups, both large and small, have the relevant expertise and could contribute to the overall effort by performing the pertinent gene function determination studies. During the course of the project it is anticipated that at least 100 gene families will be identified and subjected to experimental tests, directly affecting the annotations of thousands of important genes. The initial project will fund 40 teams across the US, and will create more than 40 new jobs providing a significant economic stimulus. It will also stream-line and integrate the process of computational predictions and biochemical function validation leading to significant improvement in the cost of future work. In addition to direct benefits to microbial biology, infectious disease research and computational biology this public experiment in the form of a new social network might have long-term transformative implications for funding and other economic implications. PUBLIC HEALTH RELEVANCE: This project will be important in providing fundamental knowledge to many aspects of infectious disease research. Unknown genes from several important pathogens such as Mycobacterium tuberculosis and Helicobacter pylori will be high priority targets as will genes in model organisms with orthologous genes that are widely distributed in both bacterial pathogens and higher organisms including humans. A key factor in deciding priorities will be the health implications of successful predictions.